The present invention relates to aryl oxime-piperazine derivatives useful as selective CCR5 antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds. The invention also relates to the use of a combination of a CCR5 antagonist of this invention and one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus (HIV). The invention further relates to the use of a CCR5 antagonist of this invention, alone or in combination with another agent, in the treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis.
The global health crisis caused by HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS), is unquestioned, and while recent advances in drug therapies have been successful in slowing the progression of AIDS, there is still a need to find a safer, more efficient, less expensive way to control the virus.
It has been reported that the CCR5 gene plays a role in resistance to HIV infection. HIV infection begins by attachment of the virus to a target cell membrane through interaction with the cellular receptor CD4 and a secondary chemokine co-receptor molecule, and proceeds by replication and dissemination of infected cells through the blood and other tissue. There are various chemokine receptors, but for macrophage-tropic HIV, believed to be the key pathogenic strain that replicates in vivo in the early stages of infection, the principal chemokine receptor required for the entry of HIV into the cell is CCR5. Therefore, interfering with the interaction between the viral receptor CCR5 and HIV can block HIV entry into the cell. The present invention relates to small molecules which are CCR5 antagonists.
CCR5 receptors have been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
A-M. Vandamme et al., Antiviral Chemistry and Chemotherapy, 9:187 (1998) 203 disclose current clinical treatments of HIV-1 infections in man including at least triple drug combinations or so-called Highly Active Antiretroviral Therapy (xe2x80x9cHAARTxe2x80x9d); HAART involves various combinations of nucleoside reverse transcriptase inhibitors (xe2x80x9cNRTIxe2x80x9d), non-nucleoside reverse transcriptase inhibitors (xe2x80x9cNNRTIxe2x80x9d) and HIV protease inhibitors (xe2x80x9cPIxe2x80x9d). In compliant drug-naive patients, HAART is effective in reducing mortality and progression of HIV-1 to AIDS. However, these multidrug therapies do not eliminate HIV-1 and long-term treatment usually results in multidrug resistance. Development of new drug therapies to provide better HIV-1 treatment remains a priority.
In its many embodiments, the present invention provides a novel class of compounds as antagonists of the CCR5 receptor, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the CCR5 receptor. In one embodiment, the present application discloses a compound, including enantiomers, stereoisomers, rotamers, tautomers, racemates and prodrug of said compound, and pharmaceutically acceptable salts or solvates of said compound or of said prodrug, said compound having the general structure shown in formula I: 
wherein:
X is-selected from the group consisting of H; F; Cl; Br; I; xe2x80x94CF3; xe2x80x94CF3O; xe2x80x94CN; CH3SO2xe2x80x94; and CF3SO2xe2x80x94;
R1 is H; straight chain alkyl or a branched alkyl; fluoro-C1-C6 alkyl; a C1-C6 alkylene carrying a C3-C7 cycloalkyl (for example, cyclopropylmethyl);
xe2x80x94CH2CH2OH; xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(C1-C6)alkyl; xe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(C1xe2x80x94C6)alkyl;
xe2x80x94CH2C(O)NH2; xe2x80x94CH2C(O)xe2x80x94NH(C1-C6)alkyl; or xe2x80x94CH2C(O)xe2x80x94N((C1xe2x80x94C6)alkyl)2;
R2 is H; a C1-C6 straight chain alkyl or a branched alkyl; or a C2-C6 alkenyl;
R3 is a C1-C6 straight chain alkyl or branched alkyl; phenyl substituted with R4, R5, R6; 6-membered heteroaryl substituted with R4, R5, R6; 6-membered heteroaryl N-oxide substituted with R4, R5, R6; 5-membered heteroaryl substituted with R7, R8; naphthyl; fluorenyl; diphenylmethyl; 
R4 and R5 may be the same or different and are independently selected from the group consisting of (C1-C6)alkyl, halogen, xe2x80x94NR12R13, xe2x80x94OH, xe2x80x94CF3,xe2x80x94OCH3, xe2x80x94O-acyl, xe2x80x94OCF3 and xe2x80x94Si(CH3)3;
R6 is R4; hydrogen; phenyl; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CH2F; xe2x80x94CHF2; xe2x80x94CHO; xe2x80x94CHxe2x95x90NOR12; pyridyl; pyridyl N-oxide; pyrimidinyl; pyrazinyl; xe2x80x94N(R12)CONR13R14; xe2x80x94N HCONH(chloroxe2x80x94(C1-C6)alkyl); xe2x80x94NHCONH((C3-C10)cycloalkyl(C1-C6)alkyl); xe2x80x94NHCO(C1-C6)alkyl; xe2x80x94NHCOCF3; xe2x80x94NHSO2N((C1-C6)alkyl)2; xe2x80x94NHSO2(C1-C6)alkyl; xe2x80x94N(SO2CF3)2; xe2x80x94N HCO2(C1-C6)alkyl); C3-C10 cycloalkyl; xe2x80x94SR15; xe2x80x94SOR15; xe2x80x94SO2R15; xe2x80x94SO2NH(C1-C6 alkyl); xe2x80x94OSO2(C1-C6)alkyl; xe2x80x94OSO2CF3; hydroxy(C1-C6)alkyl; xe2x80x94CON R12R13; xe2x80x94CON(CH2CH2xe2x80x94Oxe2x80x94CH3)2; xe2x80x94OCONH(C1-C6)alkyl; xe2x80x94CO2R2; xe2x80x94Si(CH3)3 or xe2x80x94B(OC(CH3)2)2;
R7 is (C1-C6)alkyl, xe2x80x94NH2 or R9-phenyl;
R9 is 1 to 3 substituents which may be the same or different and are independently selected from the group consisting of hydrogen, (C1-C6) alkyl, xe2x80x94CF3, xe2x80x94CO2R12, xe2x80x94CN, (C1-C6)alkoxy and halogen;
R10 and R11 may be the same or different and are independently selected from the group consisting of hydrogen and C1-C6 alkyl, or R10 and R11 together are a C2-C5 alkylene group and with the carbon to which they are attached form a spiro ring of 3 to 6 carbon atoms;
R12, R13 and R14 may be the same or different and are independently selected from the group consisting of H and C1-C6 alkyl; and
R15 is C1-C6 alkyl or phenyl.
Preferred are compounds of formula I wherein R1 is a C1-C6 straight chain alkyl or branched alkyl, with methyl and ethyl being more preferred moieties for R1.
Preferred moieties for X are: halogen, xe2x80x94CF3 and xe2x80x94CF3O.
Preferred definition for R2 is a C1-C6 straight chain alkyl or branched alkyl, with methyl being more preferred.
Preferred definitions for R3 is 2,6-dialkylaryl or 2,6-dialkylheteroaryl, with the more preferred moieties for R3 being: 
and N-oxides thereof.
Another aspect of the invention is a pharmaceutical composition for treatment of HIV comprising an effective amount of a CCR5 antagonist of formula I in combination with a pharmaceutically acceptable carrier.
One more aspect of the invention is a pharmaceutical composition for treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising an effective amount of a CCR5 antagonist of formula I in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treatment of HIV comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I.
Another aspect of the invention is a method of treatment of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allergies or multiple sclerosis comprising administering to a human in need of such treatment an effective amount of a CCR5 antagonist compound of formula I.
Still another aspect of this invention is the use of a CCR5 antagonist of formula I of this invention in combination with one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus for the treatment of AIDS.
Still another aspect of this invention is the use of a CCR5 antagonist of formula I of this invention in combination with one or more other agents useful in the treatment of solid organ transplant rejection, graft v. host disease, inflammatory bowel disease, rheumatoid arthritis or multiple sclerosis. The CCR5 and antiviral or other agents which are components of the combination can be administered in a single dosage form or they can be administered separately; a kit comprising separate dosage forms of the actives is also contemplated.
As used herein, the following terms are used as defined below unless otherwise indicated.
Alkyl (including the alkyl portions of alkoxy, alkylamino and dialkylamino) represents straight and branched carbon chains and contains from one to six carbon atoms.
Alkenyl represents C2-C6 carbon chains having one or two unsaturated bonds, provided that two unsaturated bonds are not adjacent to each other.
Substituted phenyl means that the phenyl group can be substituted at any available position on the phenyl ring.
Acyl means a radical of a carboxylic acid having the formula alkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, aralkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-C(O)xe2x80x94, (C3-C7)cycloalkyl-(C1-C6)alkyl-C(O)xe2x80x94, and heteroaryl xe2x80x94C(O)xe2x80x94, wherein alkyl and heteroaryl are as defined herein; aryl is R12-phenyl or R12-naphthyl; and aralkyl is aryl-(C1-C6)alkyl, wherein aryl is as defined above.
Heteroaryl represents cyclic aromatic groups of 5 or 6 atoms or bicyclic groups of 11 to 12 atoms having 1 or 2 heteroatoms independently selected from O, S or N, said heteroatom(s) interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, provided that the rings do not contain adjacent oxygen and/or sulfur atoms. For 6-membered heteroaryl rings, carbon atoms can be substituted by alkyl or similar groups. Nitrogen atoms can form an N-oxide. All regioisomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Typical 6-membered heteroaryl groups are pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and the N-oxides thereof. For 5-membered heteroaryl rings, carbon atoms can be substituted by alkyl or similar groups. Typical 5-membered heteroaryl rings are furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. 5-Membered rings having one heteroatom can be joined through the 2- or 3-position; 5-membered rings having two heteroatoms are preferably joined through the 4-position. Bicyclic groups typically are benzo-fused ring systems derived from the heteroaryl groups named above, e.g. quinolyl, phthalazinyl, quinazolinyl, benzofuranyl, benzothienyl and indolyl.
Halogen represents fluoro, chloro, bromo and iodo.
Fluoro(C1-C6)alkyl represents a straight or branched alkyl chain substituted by 1 to 5 fluoro atoms, which can be attached to the same or different carbon atoms, e.g., xe2x80x94CH2F, xe2x80x94CHF2, xe2x80x94CF3, F3CCH2xe2x80x94and xe2x80x94CF2CF3.
A therapeutically effective amount of a CCR5 antagonist is an amount sufficient to lower HIV-1-RNA plasma levels.
One or more, preferably one to four, antiviral agents useful in anti-HIV-1 therapy may be used in combination with a CCR5 antagonist of the present invention. The antiviral agent or agents may be combined with the CCR5 antagonist in a single dosage form, or the CCR5 antagonist and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms. The antiviral agents contemplated for use in combination with the compounds of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and other antiviral drugs listed below not falling within these classifications. In particular, the combinations known as HAART are contemplated for use in combination with the CCR5 antagonists of this invention.
The term xe2x80x9cnucleoside and nucleotide reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNRTIxe2x80x9ds) as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV-1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA.
Typical suitable NRTIs include zidovudine (AZT) available under the RETROVIR tradename from Glaxo SmithKline, Research Triangle Park, N.C.; didanosine (ddl) available under the VIDEX tradename from Bristol-Myers Squibb Company, Princeton, N.J.; zalcitabine (ddC) available under the HIVID tradename from Roche Pharmaceuticals, Nutley, N.J. stavudine (d4T) available under the ZERIT trademark from Bristol-Myers Squibb Company; lamivudine (3TC) available under the EPIVIR tradename from Glaxo SmithKline; abacavir (1592U89) disclosed in WO96/30025 and available under the ZIAGEN trademark from Glaxo SmithKline; adefovir dipivoxil [bis(POM)-PMEA] available under the PREVON tradename from Gilead Sciences, Foster City, Calif.; lobucavir (BMS-180194), a nucleoside reverse transcriptase inhibitor disclosed in EP-0358154 and EP-0736533 and under development by Bristol-Myers Squibb Company; BCH-10652, a reverse transcriptase inhibitor (in the form of a racemic mixture of BCH-10618 and BCH-10619) under development by Biochem Pharma, Laval, Quebec, Canada; emitricitabine [(xe2x88x92)xe2x88x92FTC] licensed from Emory University under Emory Univ. U.S. Pat. No. 5,814,639 and under development by Triangle Pharmaceuticals, Durham, N.C.; beta-L-FD4 (also called beta-L-D4C and named beta-L-2xe2x80x2, 3xe2x80x2-dicleoxy-5-fluoro-cytidene) licensed by Yale University to Vion Pharmaceuticals, New Haven, Conn.; DAPD, the purine nucleoside, (xe2x88x92)xe2x88x92beta-D-2,6,-diamino-purine dioxolane disclosed in EP 0656778 and licensed by Emory University and the University of Georgia to Triangle Pharmaceuticals; and lodenosine (FddA), 9-(2,3-dideoxy-2-fluoro-b-D-threo-pentofuranosyl)adenine, an acid stable purine-based reverse transcriptase inhibitor discovered by the NIH and under development by U.S. Bioscience Inc., West Conshohoken, Pen.
The term xe2x80x9cnon-nucleoside reverse transcriptase inhibitorsxe2x80x9d (xe2x80x9cNNRTIxe2x80x9ds) as used herein means non-nucleosides that inhibit the activity of HIV-1 reverse transcriptase.
Typical suitable NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, Ohio; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia Corporation, Bridgewater, Bridgewater, N.J.; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, Del.; PNU-142721, a furopyridine-thio-pyrimide under development by Pharmacia Corporation; AG-1549 (formerly Shionogi # S-1153); 5-(3,5-dichlorophenyl)-thio-4-isopropyl-1-(4-pyridyl)methyl-IH-imidazol-2-ylmethyl carbonate disclosed in WO 96/10019 and under clinical development by Agouron Pharmaceuticals, Inc., LaJolla, Calif.; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione) discovered by Mitsubishi Chemical Co. and under development by Triangle Pharmaceuticals; and (+)-calanolide A (NSC-675451) and B, coumarin derivatives disclosed in NIH U.S. Pat. No. 5,489,697, licensed to Med Chem Research, which is co-developing (+) calanolide A with Vita-Invest as an orally administrable product.
The term xe2x80x9cprotease inhibitorxe2x80x9d (xe2x80x9cPIxe2x80x9d) as used herein means inhibitors of the HIV-1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1. HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN (available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT (available from Agouron).
Typical suitable Pls include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE tradename and as soft gel capsules under the FORTOVASE tradename from Roche Pharmaceuticals, Nutley, N.J.; ritonavir (ABT-538) available under the NORVIR tradename from Abbott Laboratories, Abbott Park, Ill.; indinavir (MK-639) available under the CRIXIVAN tradename from Merck and Co., Inc; nelfnavir (AG-1343) available under the VIRACEPT tradename from Agouron Pharmaceuticals, Inc; amprenavir (141W94), tradename AGENERASE, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, Mass. and available from Glaxo SmithKline, Research Triangle Park under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by DuPont and under development by Triangle Pharmaceuticals; BMS-2322623, an azapeptide under development by Bristol-Myers Squibb as a 2nd-generation HIV-1 PI; ABT-378 under development by Abbott Laboratories; and AG-1 549 an orally active imidazole carbamate discovered by Shionogi (Shionogi #S-1153) and under development by Agouron Pharmaceuticals, Inc.
Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.11607. Hydroyurea (Droxia), a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI and is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine. IL-2 is disclosed in Ajinomoto EP-0142268, Takeda EP-0176299, and Chiron U.S. Pat. Nos. RE 33653,4530787, 4569790, 4604377, 4748234,4752585, and 4949314, and is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, Calif., as a lyophilized powder for IV infusion or subcutaneous (xe2x80x9cscxe2x80x9d) administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred. IL-12 is disclosed in WO96/25171 and is available from Roche Pharmaceuticals, and American Home Products, Madison, N.J.; dose of about 0.5 microgram/kg/day to about 10 microgram/kg/day, sc is preferred. Pentafuside (DP-178, T-20) a 36-amino acid synthetic peptide, disclosed in U.S. Pat. No. 5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes. Pentafuside (3-100 mg/day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI""s to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred. Yissum Project No. 11607, a synthetic protein based on the HIV-1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042, Israel. Ribavirin, 1-xcex2-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; its manufacture and formulation are described in U.S. Pat. No. 4,211,771.
The term xe2x80x9canti-HIV-1 therapyxe2x80x9d as used herein means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part of multidrug combination therapies, especially the HAART triple and quadruple combination therapies. Typical suitable known anti-HIV-1 therapies include, but are not limited to, multidrug combination therapies such as (i) at least three anti-HIV-1 drugs selected from two NRTIs, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from NNRTIs and PIs. Typical suitable HAARTxe2x80x94multidrug combination therapies include:
(a) triple combination therapies such as two NRTIs and one PI; or (b) two NRTIs and one NNRTI; and (c) quadruple combination therapies such as two NRTIs, one PI and a second PI or one NNRTI. In treatment of naive patients, it is preferred to start anti-HIV-1 treatment with the triple combination therapy; the use of two NRTIs and one PI is preferred unless there is intolerance to PIs. Drug compliance is essential. The CD4+ and HIV-1-RNA plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug, e.g., one PI or one NNRTI could be added. The table below further describes typical illustrative therapies:
A. Triple Combination Therapies
1. Two NRTIs1+one PI2 
2. Two NRTIs1+one NNRTI3 
B. Quadruple Combination Therapies4 
Two NRTIs+one PI+a second PI or one NNRTI
C. Alternatives:5 
Two NRTI1 
One NRTI5+one PI2 
Two PIs6xc2x1one NRTI7 or NNRTI3 
One PI2+one NRTI7+one NNRTI3 
Footnotes to Table
1. One of the following: zidovudine+lamivudine; zidovudine+didanosine; stavudine+lamivudine; stavudine+didanosine; zidovudine+zalcitabine
2. Indinavir, nelfinavir, ritonavir or saquinavir soft gel capsules.
3. Nevirapine or delavirdine.
4. See A-M. Vandamne et al, Antiviral Chemistry and Chemotherapy 9:187 at p 193-197 and FIGS. 1+2.
5. Alternative regimens are for patients unable to take a recommended regimen because of compliance problems or toxicity, and for those who fail or relapse on a recommended regimen. Double nucleoside combinations may lead to HIV-resistance and clinical failure in many patients.
6. Most data obtained with saquinavir and ritonavir (each 400 mg bid).
7. Zidovudine, stavudine or didanosine.
Agents known in the treatment of rheumatoid arthritis, transplant and graft v. host disease, inflammatory bowel disease and multiple sclerosis which can be administered in combination with the CCR5 antagonists of the present invention are as follows:
solid organ transplant rejection and graft v. host disease: immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;
inflammatory bowel disease: IL-10 (see U.S. Pat. No. 5,368,854), steroids and azulfidine;
rheumatoid arthritis: methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil;
multiple sclerosis: interferon-beta, interferon-alpha, and steroids.
Certain CCR5 antagonist compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers and atropisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures.
Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
Certain basic compounds also form pharmaceutically acceptable salts, e.g., acid addition salts. For example, the pyrido-nitrogen atoms may form salts with strong acid, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise equivalent to their respective free base forms for purposes of the invention.
All such acid and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Compounds of the invention can be made by the procedures known in the art as well as by the procedures described in the following reaction schemes and by the methods described in the examples below.
The following solvents and reagents may be referred to herein by the abbreviations indicated: tetrahydrofuran (THF); ethanol (EtOH); methanol (MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc); N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroacetic anhydride (TFAA); 1-hydroxy-benzotriazole (HOBT); m-chloroperbenzoic acid (MCPBA); triethylamine (Et3N); diethyl ether (Et2O); tert-butoxy-carbonyl (BOC); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); dimethyl-sulfoxide (DMSO); p-toluene sulfonic acid (p-TSA); potassium bis(trimethylsilyl)-amide (KHMDA); 4-dimethylaminopryidine (DMAP); N,N,N-diiospropylethylamine (Dipea); and 1-(3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride (DEC). RT is room temperature.
Preparations:
Compounds of this invention are prepared using either of the following general procedures:
Method 1:
When R3 and the carbonyl group to which it is attached are derived from 4,6-dimethyl-pyrimidine-5-carboxylic acid, then the method described in Scheme 1 is used. Compound 1, prepared as described in WO-00066558, is converted to intermediate 2 by hydrogenolysis over a suitable catalyst such as palladium hydroxide and also in the presence of a hydrogen source such as hydrogen gas or ammonium formate. Compound 2 is heated in the presence of a hydroximinochloride 3 either neat or in the presence of a solvent such as dichloromethane and optionally in the presence of a base such as diethyl isopropylamine to give 4 (=I with R1=H). Compound 4 is treated with a suitable alkylating agent such as an alkyl halide or alkyl methanesulfonate in the presence of a base such as potassium hydroxide, and preferably in a solvent such as toluene and in the presence of a phase-transfer catalyst such as tetrabutylammonium bromide to give compound I. 
More generally, compounds I with a variety of groups R3 can be prepared as described in Scheme 2. Intermediate 5 is transformed to 6 and then optionally alkylated in a similar manner to the procedure described in Scheme 1. The Boc protecting group is removed under standard conditions to give 7, which is then coupled with a suitable carboxylic acid using standard procedures well known to those skilled in the art. 